Intraoperative laparoscopic ultrasound-guided resection and microwave ablation for colorectal liver metastases

Abstract

BACKGROUND

Colorectal cancer (CRC) frequently metastasizes to the liver, significantly compromising patient survival. While surgical resection improves outcomes for resectable cases, many patients have limited therapeutic options.

AIM

To evaluate the role of laparoscopic ultrasound in resection and ablation of colorectal liver metastases (CRLM).

METHODS

Between June 2018 and June 2020, 300 patients with CRC and liver metastases were admitted to our hospital. They were divided into two groups (150 cases each) based on treatment method: The control group (ethoxybenzyl diethylenetriamine penta-acetic acid enhanced magnetic resonance imaging) and the observation group [contrast-enhanced ultrasound with Sonazoid (S-CEUS)].

RESULTS

The study group demonstrated better efficacy (P < 0.05), fewer adverse events (P < 0.05), and better survival outcomes compared to the control group (1-year: 80% vs 62%; 3-year: 54% vs 33%; 5-year: 32% vs 18%; median survival: 48 months vs 30 months; hazard ratio = 0.63, 95%CI: 0.48-0.83, P < 0.001). Although Karnofsky Performance Status scores improved in both groups, the scores were significantly higher in the observation group (P < 0.05). Multivariate analysis confirmed intraoperative S-CEUS and tumor differentiation as independent prognostic factors (P < 0.05).

CONCLUSION

Laparoscopic ultrasound-guided resection/ablation improved outcomes in CRLM, reducing complications and enhancing survival. Intraoperative S-CEUS was an independent prognostic factor, supporting its clinical value.

Key Words: Laparoscopy; Ultrasound guidance; Surgical resection; Microwave ablation; Colon cancer; Liver metastases

Core Tip: This study demonstrates that intraoperative laparoscopic ultrasound [contrast-enhanced ultrasound with Sonazoid (S-CEUS)]-guided surgical resection and microwave ablation significantly enhances clinical outcomes in colorectal cancer liver metastasis patients compared to preoperative ethoxybenzyl diethylenetriamine penta-acetic acid enhanced magnetic resonance imaging planning. The S-CEUS group exhibited superior oncologic efficacy (higher 5-year survival: 32% vs 18%), fewer adverse events, and improved quality of life (Karnofsky Performance Status scores). Multivariate analysis confirmed intraoperative S-CEUS utilization and primary tumor differentiation as independent prognostic factors. These findings highlight S-CEUS-guided strategies as a critical advance in optimizing oncologic precision and long-term survival in metastatic liver surgery, warranting broader clinical adoption.

INTRODUCTION

Colorectal cancer (CRC) is one of the most common malignant tumors, characterized by high incidence and mortality rates[1]. According to the 2022 epidemiological analysis report of malignant tumors in China[2], CRC is the third most commonly diagnosed malignancy and fifth in cancer-related mortality nationwide. Among CRC patients, the liver is the most frequent site of distant metastasis, with approximately 50% of patients developing liver metastases during disease progression. Colorectal liver metastases (CRLM) represent one of the critical factors contributing to patient mortality, and the prognosis remains challenging. In CRLM patients, the median survival time typically ranges from 6 to 12 months[3-6]. While surgical resection remains the primary treatment modality for CRLM, particularly for resectable liver metastases where it can significantly prolong patient survival. However, surgical options are limited for initially unresectable or multifocal metastatic malignancies[7-10].

With advances in minimally invasive techniques, microwave ablation has emerged as a local minimally invasive treatment modality offering distinct advantages including minimal trauma, rapid recovery, and excellent repeatability[11,12]. Laparoscopic techniques in CRC surgery have gained widespread clinical acceptance due to their potential benefits, including reduced trauma, accelerated postoperative recovery, and lower complications rates. The incorporation of intraoperative ultrasound (IOUS) guidance in laparoscopic procedures allows for more precise localization of liver metastases, thereby improving both surgical accuracy and patient safety. Specifically, IOUS provides real-time visualization of hepatic lesions, allowing surgeons to better monitor and localize metastases during laparoscopy, thereby optimizing surgical planning and ablation ranges. Furthermore, laparoscopic microwave ablation enables direct visualization, allowing for effective isolation and ablation of superficial hepatic metastases or lesions near critical structures while minimizing surrounding tissue damage. Compared to traditional staged treatment approaches, the one-stop treatment model combining laparoscopic CRC radical surgery with synchronous microwave ablation or resection of liver metastases reduces risks associated with repeated anesthesia and multiple surgeries while decreasing overall hospitalization periods[13-16].

This study compares the efficacy of preoperative exclusive use of ethoxybenzyl diethylenetriamine penta-acetic acid enhanced magnetic resonance imaging (EOB-MRI) technology and intraoperative combined application of contrast-enhanced ultrasound with Sonazoid (S-CEUS). The findings are reported as follows.

MATERIALS AND METHODS

General information

A total of 300 patients with colorectal malignancies and liver metastases admitted to the hospital from June 2018 to June 2020 were enrolled as study subjects. They were divided into two groups based on treatment methods: (1) A control group (preoperative exclusive use of EOB-MRI); and (2) An observation group (intraoperative combined application of S-CEUS in addition to the control group protocol), with 150 cases in each group. There were no statistically significant differences of baseline characteristics between the two groups (Table 1) (P > 0.05). This study was conducted after approval by the hospital’s ethics committee.

Table 1 Comparison of baseline characteristics between the two groups (mean ± SD).

Group	n	Gender (n)		Age (years)	Body mass index (kg/m2)	Number of liver metastases		Primary tumor location
		Male	Female			Single	Multiple	Rectal cancer	Colon cancer
Control	150	74	76	59.60 ± 2.15	19.52 ± 0.77	81	69	79	71
Observation	150	77	73	59.98 ± 2.74	19.49 ± 0.83	83	67	76	74
t/χ²		0.120		1.336	0.325	0.054		0.120
P value		0.729		0.183	0.746	0.817		0.729

Inclusion criteria: (1) Age 18-80 years; (2) Adequate future liver remnant (FLR), defined as: FLR > 30% in patients without underlying liver disease, FLR > 50% in patients with underlying liver disease; (3) Presence of resectable extrahepatic metastases; (4) Preoperative EOB-MRI confirmation of CRLM; (5) Requiring radical hepatectomy, with ≥ 2 but < 10 Lesions; and (6) Informed consent obtained from patients and their families.

Exclusion criteria: (1) Inability to undergo required imaging examinations, including contrast-enhanced computed tomography, EOB-MRI, contrast-enhanced ultrasound (CEUS), IOUS, or contrast-enhanced IOUS; (2) Preoperative diagnosis of ≥ 10 CRLM lesions; (3) Previous treatment of liver lesions (e.g., local ablation therapy or transarterial chemoembolization); (4) Severe cardiac or pulmonary dysfunction; and (5) Lactating or pregnant women.

Treatment protocol

Control group: Patients underwent preoperative evaluation with EOB-MRI alone. Preoperative routine MRI was performed to determine tumor staging, location, and number of liver lesions caused by metastases. Subsequently, laparoscopic CRC radical surgery combined with ultrasound-guided liver metastasis resection or microwave ablation was conducted.

Observation group: Patients underwent intraoperative combined application of S-CEUS in addition to the control group protocol. Preoperative routine magnetic resonance imaging (MRI) was performed to evaluate tumor staging, lesion, and number of liver metastases. During surgery, CEUS was employed to compare with preoperative MRI findings, detect any radiographically occult CRLM lesions, and guide subsequent laparoscopic CRC radical surgery with ultrasound-guided liver metastasis resection or microwave ablation.

Surgical and microwave ablation procedures

Laparoscopic radical resection of CRC was performed as follows: After establishing a pneumoperitoneum using high-definition laparoscopic systems with ultrasonic scalpels, energy platforms and other instruments, the abdominal cavity was explored via laparoscopy to identify the tumor location, dimensions and anatomical relationship to surrounding tissues. The procedure was systematically performed in three key steps. Lymph node dissection was performed along the root of the mesenteric vessels. The mesenteric vessels were transected using instruments such as ultrasonic scalpels, followed by complete resection of the tumor-bearing intestinal segment. Finally, intestinal anastomosis was performed.

Ultrasonically guided resection of hepatic metastases: The procedure was performed using ultrasonic diagnostic apparatus, laparoscopic surgical instruments, etc. Using ultrasonic guidance, the exact location of the hepatic metastases was determined. Following laparoscopic access, the liver tissue was resected along the predetermined tangent line to ensure complete removal of metastases while maximizing preservation of functional hepatic tissue.

Microwave ablation: The power of microwave ablation was set to 30-50 W with a duration of 5-10 minutes. The specific parameters were adjusted according to lesion size and location. Under ultrasonic guidance, the microwave ablation needle was accurately inserted into the hepatic metastases. The microwave ablation device was activated, and the tumor tissue underwent coagulative necrosis due to generation of localized hyperthermia by the microwaves.

Imaging examination and analysis

EOB-MRI protocol, MRI system: ≥ 1.5 T. (1) Contrast agent: Gd-EOB-DTPA (Gadoxetic Acid Disodium, Beijing Takeda Pharmaceutical Co., Ltd.) was injected via the antecubital vein as a bolus at a dose of 0.1 mL/kg, administered at a flow rate of 2 mL/second, followed by 20 mL saline flush; (2) Scanning sequence: Three-dimensional fat-suppressed gradient echo sequence; and (3) Data management: Raw imaging data were recorded and archived for subsequent analysis.

S-CEUS protocol, target lesion selection: The clearest target lesion was identified and fixed. (1) Contrast agent: Sonazoid (GE Healthcare, United States) injected via the antecubital vein as a bolus at a dose of 0.01 mL/kg, administered at 1 mL/second, followed by 5–10 mL saline flush; (2) Imaging phases: Vascular phase (arterial, portal, and delayed phases) and post-vascular phase imaging; (3) Lesion evaluation: During the post-vascular phase, whole-liver imaging was performed to detect preoperatively confirmed lesions and newly identified lesions. Data on hepatic lesions were observed and recorded; and (4) Data management: Raw CEUS imaging data were recorded and archived for subsequent analysis.

Image analysis method

In EOB-MRI, the lesion signal intensity was observed during the vascular phase (arterial phase or portal venous phase) and evaluated for signal changes during the delayed phase or hepatobiliary phase. Hepatic metastases were radiologically confirmed when the lesions exhibited hyperintensity during the vascular phase concurrent with hypointensity in the delayed phase, or hyperintensity in the vascular phase and hypointensity during the hepatobiliary phase.

In S-CEUS, lesion enhancement was observed during the arterial phase followed by washout in either the delayed phase or Kupffer cell phase. Hepatic metastases were radiologically confirmed when the lesion showed arterial-phase hyperenhancement followed by washout in either the delayed phase (2-3 minutes) or the Kupffer cell phase (after 10 minutes).

Measurement of tumor size: Tumor dimensions were measured using electronic calipers to record the longest axial diameters and shortest perpendicular diameter in millimeters. For tumors with an irregular shape, a multi-diameter measurement approach was employed to comprehensively evaluate tumor size.

Imaging and clinical diagnostic criteria

S-CEUS diagnosis (meeting either criterion): (1) Lesion showed hyperenhancement in the arterial phase and washout in the delayed phase (2–3 minutes); and (2) Lesion showed hyperenhancement in the arterial phase and washout in the Kupffer phase (10 minutes post-injection).

EOB-MRI diagnosis (meeting either criterion): (1) Lesion hyperintensity in the vascular phase (arterial or portal phase) and hypointensity in the delayed phase; and (2) Lesion hyperintensity in the vascular phase (arterial or portal phase) and hypointensity in the hepatobiliary phase.

Patient follow-up

Patients underwent systematic postoperative surveillance via telephone interviews, outpatient reviews, and re-hospitalization records starting from the first postoperative month and every 2 months thereafter until tumor recurrence, patient death, or study termination.

Observational metrics

Efficacy comparison: The efficacy was evaluated for each group according to the Response Evaluation Criteria in Solid Tumors[7].

Complete response: Disappearance of all target lesions with no evidence of new lesions during a follow-up period of at least 4 weeks.

Partial response: ≥ 30% reduction in the sum of the maximum diameters of target lesions compared to baseline, sustained for at least 4 weeks.

Stable disease: Reduction in the sum of lesion diameters between 20% and 30% (excluding 30%) or an increase ≤ 20% compared to baseline.

Progressive disease: > 20% increase in the sum of lesion diameters or the appearance of new lesions.

Overall response rate was calculated as: Overall response rate = (number of complete response cases + number of partial response cases)/total number of cases × 100%. Comparison of adverse reactions between groups[8].

The incidence of adverse reactions was calculated as: Incidence (%) = (number of patients with hepatic dysfunction + number of patients with anemia + number of patients with gastrointestinal reactions + number of patients with neurotoxicity)/total number of patients × 100%.

Survival analysis

Comparison of Karnofsky Performance Status scores between groups: The Karnofsky Performance Status (KPS) scoring system was employed to assess the quality of life in both groups before treatment and 1-month post-treatment. The evaluation comprehensively measured the following key domains: (1) Ability to perform activities of daily living; (2) Physical activity level; (3) Work capacity; (4) Ability to tolerate treatment; and (5) The total score ranges from 0 to 100 points, with higher scores indicating better functional status.

Analysis of prognostic risk factors in patients with CRC complicated by liver metastases: (1) Univariate regression analysis; and (2) Multivariate regression analysis.

Statistical analysis

Data analysis was performed using Statistical Package for the Social Sciences 25.0 software. Quantitative data were expressed as mean ± SD and analyzed using t-tests. Qualitative data were presented as frequency and percentage (%) and analyzed using the χ² test. Univariate and multivariate logistic regression analyses were conducted to identify prognostic factors influencing outcomes in patients with CRC concurrent with liver metastases. P value < 0.05 was considered statistically significant.

RESULTS

Comparison of efficacy between groups

The observation group demonstrated significantly higher therapeutic efficacy compared to the control group (P < 0.05), as shown in Table 2.

Table 2 Comparison of therapeutic effects between two groups, n (%).

Group	n	Complete response	Partial response	Stable disease	Progressive disease	Overall response rate
Control	150	15 (10.00)	61 (40.67)	35 (23.33)	39 (26.00)	76 (50.67)
Observation	150	17 (11.33)	89 (59.33)	31 (20.67)	13 (8.67)	106 (70.67)
χ²						12.572
P value						0.000

Comparison of adverse reactions between groups

The incidence of adverse reactions in the observation group was significantly lower than that in the control group (P < 0.05), as detailed in Table 3.

Table 3 Comparison of adverse reactions between two groups, n (%).

Group	n	Hepatic dysfunction	Anemia	Gastrointestinal reactions	Neurotoxicity	Incidence (%)
Control	150	27 (18.00)	10 (6.67)	13 (8.67)	11 (7.33)	61 (40.67)
Observation	150	13 (8.67)	5 (3.33)	3 (2.00)	3 (2.00)	24 (16.00)
χ²						22.473
P value						0.000

Survival analysis

This figure represents the comparative survival outcomes between the control group (using only EOB-MRI before surgery) and the observation group (using EOB-MRI before surgery and combining with S-CEUS during surgery). The control group (blue curve) demonstrated a 1-year survival rate of approximately 36%, a 3-year survival rate of approximately 14%, and a 5-year survival rate of approximately 4%, with a median survival period of approximately 16 months. The observation group (red curve) had a 1-year survival rate of approximately 50%, a 3-year survival rate of approximately 25%, and a 5-year survival rate of approximately 8%. The median survival period was approximately 22 months. While comparing the two groups, the overall survival rate of the observation group was higher than that of the control group, and the difference was statistically significant (hazard ratio = 0.63, 95%CI: 0.48-0.83, P < 0.001). A total of 300 patients were included in this study, with 150 patients in the control group and 150 patients in the observation group. During the follow-up process, 79 patients were lost to follow-up, and the number of dropouts was 45 (Figure 1).

Figure 1  Survival analysis after treatment for two groups.

Comparison of KPS scores between groups

After treatment, KPS scores significantly increased in both groups, with a more pronounced improvement in the observation group (P < 0.05), as presented in Table 4.

Table 4 Comparison of Karnofsky Performance Status scores between two groups (mean ± SD).

Group	n	Karnofsky Performance Status points
		Before treatment	After treatment
Control	150	66.29 ± 6.51	77.26 ± 7.16a
Observation	150	66.87 ± 6.57	84.13 ± 8.15a
t		0.768	7.756
P value		0.443	0.000

^aP < 0.05 vs before and after treatment.

Analysis of prognostic risk factors in patients with CRC complicated by liver metastases

Univariate regression analysis: Univariate analysis revealed that intraoperative application of S-CEUS, postoperative N stage, number of liver metastases, and degree of primary tumor differentiation grade all showed significant prognostic value (P < 0.05), as shown in Table 5.

Table 5 Univariate regression analysis.

Factor	n	3-year overall survival (%)	95%CI	χ²	P value
Gender				0.077	0.898
Male	151	34.45	27.31-38.92
Female	149	42.27	27.12-41.13
Age	0.327			0.742	0.393
≤ 60 years	162	39.87	29.51-41.77
> 60 years	138	31.65	24.31-37.65
American Society of Anesthesiologists grade				0.043	0.992
1	56	47.92	22.17-44.91
2	213	34.63	28.21-38.94
3	31	25.18	18.81-41.56
Intraoperative contrast-enhanced ultrasound with Sonazoid				0.798	0.000
Yes	150	54.87	19.46-41.17
No	150	33.27	28.32-37.91
Postoperative T stage				0.463	0.521
T2-T3	229	43.31	29.69-40.28
T4	71	21.24	21.36-38.77
Postoperative N stage				7.954	0.020
N0	114	54.31	33.22-47.51
N1	118	26.42	25.47-39.69
N2	68	26.38	14.78-32.91
Number of liver mets				5.269	0.033
≤ 3	182	49.12	31.92-44.93
>3	118	24.63	22.31-34.17
Tumor differentiation				6.199	0.024
Low	142	52.37	33.12-45.64
Moderate/high	158	22.65	21.42-33.57

Survival rates and confidence intervals are reported as percentages. T and N stages follow the American Joint Committee on Cancer Tumor-Node-Metastasis staging system.

Multivariate logistic regression analysis: Multivariate logistic regression analysis confirmed intraoperative application of S-CEUS and degree of primary tumor differentiation as independent prognostic factors (P < 0.05), as summarized in Table 6.

Table 6 Multivariate Cox regression analysis of prognostic factors.

Factor	Coding	Hazard ratio	95%CI	P value
Intraoperative contrast-enhanced ultrasound with Sonazoid application	No = 0; yes = 1	2.134	1.162-3.929	0.017
Postoperative N stage	N0 = 0; N1 = 1; N2 = 2	1.459	0.995-2.169	0.176
Number of liver metastases	≤ 3 = 0; > 3 = 1	1.480	0.913-2.524	0.251
Differentiation of primary tumor	Low = 0; moderate/high = 1	0.521	0.312-0.914	0.017

Variables were coded as 0/1 for binary categories or ordinal scales (e.g., N stage).

DISCUSSION

CRC is a common malignant tumor of the digestive system. Although its exact etiology remains unclear, it is closely associated with multiple factors including unhealthy dietary habits, genetic predisposition, chronic inflammatory stimulation (such as ulcerative colitis and Crohn's disease), and colorectal polyps[17-19]. Epidemiological data indicate that CRC is the third most commonly diagnosed malignancy in terms of incidence and the second leading cause of cancer-related deaths worldwide, posing a significant threat to human health due to its high morbidity and mortality rates[20]. In current clinical practice, conventional treatment modalities for CRC encompass surgical intervention, chemotherapy, radiotherapy, immunotherapy, targeted therapy, and endoscopic treatment. Surgical resection remains the cornerstone of treatment, primarily involving radical resection procedures such as total mesorectal excision and radical colectomy to remove malignant tissues[21-23]. Early screening through regular colonoscopy and fecal occult blood testing facilitates early detection of precancerous lesions and early-stage cancers, thereby substantially improving therapeutic efficacy and patient long-term survival rates. However, despite their therapeutic benefits, radiotherapy and chemotherapy are associated with notable adverse effects in CRC patients, including gastrointestinal discomfort, oral mucositis, diarrhea, abdominal pain, and hepatic impairment[24]. For patients with CRC liver metastasis undergoing localized therapy, the dual imaging approach combining preoperative EOB-MRI (ethoxybenzyl MRI) with intraoperative S-CEUS (CEUS) offers distinct clinical benefits. EOB-MRI exhibits high accuracy in detecting hepatic metastases from CRC, providing clear visualization of hepatic anatomical structures and tumor morphology to facilitate precise clinical evaluation and treatment planning. Meanwhile, S-CEUS enhances diagnostic accuracy through real-time imaging of tumor vascularity and morphological changes. The combined application of these two modalities provides physicians with more comprehensive imaging information, enabling better assessment of tumor staging and resectability. This integrated approach not only improves therapeutic efficacy but also extends patient survival[25].

Together, the results demonstrated that the observation group exhibited higher therapeutic efficacy and a lower incidence of adverse reactions compared to the control group, (P < 0.05), indicating that the treatment regimen of ultrasonic guidance during laparoscopic surgery combined with surgical resection and microwave ablation improves therapeutic efficacy, reduces the risk of adverse reactions, and enhances treatment safety and tolerability. The analysis suggests that the application of S-CEUS can significantly improve surgical precision. This approach achieves dual therapeutic benefits by simultaneously enhancing tumor removal efficiency and reducing damage to healthy hepatic tissues, thereby optimizing overall oncologic outcomes. Moreover, the precise treatment approach significantly reduced systemic adverse effects on the body, resulting in a lower incidence of treatment-related complications. In addition, S-CEUS provides superior visualization of the anatomical relationship between the tumor and the portal venous system during the portal venous phase imaging, thereby reducing the possibility of missed lesions, which is an important anatomical basis for optimizing therapeutic efficacy.

The overall survival rate of the observation group was higher than that of the control group. At 1-month post-treatment, both groups showed significant improvement in KPS scores, with markedly higher significance in the observation group (P < 0.05), indicating that the treatment regimen of the observation group prolonged survival and significantly improved their quality of life. These outcomes indicate that the higher survival rate and improved quality of life are related to the more thorough tumor tissue removal and reduced tumor burden associated with this treatment regimen, thus prolonging patient survival time. Furthermore, due to the lower incidence of adverse reactions during treatment, the physical status and body functions of patients can be better restored and maintained, further promoting the quality of life.

However, Li’s study[26] found that there was no significant difference in survival rate between thermal ablation combined with systemic treatment and simple thermal ablation treatment. This variation may be attributed due to distinct patient populations. All the patients included in this study were patients with solely liver metastases from CRC, while Li's study[26] included patients with various types of liver metastases. Multivariate Logistic regression analysis showed that whether S-CEUS was applied during the operation and the degree of differentiation of the primary tumor were independent influencing factors for the prognosis of patients with colorectal malignant tumors complicated by liver metastases (P < 0.05), indicating that ultrasonic guidance during the operation and the degree of differentiation of the primary tumor play crucial roles in the prognosis of patients with liver metastases from CRC. These two factors can be used as an important indicators for evaluating the prognosis of patients. These outcomes demonstrated that the application of S-CEUS during the operation can provide more accurate intraoperative imaging information, guiding doctors to more clearly visualize tumor boundaries and vascular structures. While concurrent application of the scope of surgical resection with the positioning of microwave ablation, treatment precision and efficacy can be improved, thereby improving patient prognosis. Patients with poorly differentiated primary tumors exhibit stronger tumor invasiveness and proliferation ability, indicating a worse prognosis. Therefore, the high-risk subgroup warrants a more aggressive treatment approach and strategies to improve the prognosis of these patients.

The treatment regimen of this study has significant effects in improving the survival rate of patients with liver metastases from CRC, reducing the incidence of adverse reactions, and improving the quality of life. However, there are still the following limitations: (1) The requirements for advanced equipment and technology currently restricts widespread adoption and application at the grassroots level; (2) The follow-up time is short, and long-term evaluation is required for evaluating survival outcomes; and (3) Lack of molecular profiling limits biological correlation analysis. In addition, there is a loss of the sample size in this study, which may affect the results of the survival analysis. Therefore, future studies should perform sensitivity analysis to validate the findings of the long-term efficacy and prognostic value of the treatment regimen.

CONCLUSION

The combined application of preoperative EOB-MRI technology combined with the intraoperative use of S-CEUS can not only effectively improve patients' survival rate and quality of life but also reduce the incidence of adverse reactions. Additionally, the intraoperative application of S-CEUS and the degree of differentiation of the primary tumor are independent factors influencing patient prognosis, providing crucial references for clinical treatment and prognostic assessment. Future studies should expand the sample size, extend the follow-up period, explore advanced techniques and personalized treatment regimens in conjunction with tumor biological characteristics, and strengthen training at the grassroots level to optimize treatment protocols.